Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the r-enantiomer and methods of use

ABSTRACT

Ketogenic compositions include a non-racemic mixture of beta-hydroxybutyrate salts and acid(s) enriched with the R-enantiomer. The compositions are enriched with the R-enantiomer to elevate ketone bodies and increase the rate at which ketosis is achieved yet contains an amount of the S-enantiomer to provide alternative benefits. Beta-hydroxybutyric acid is more rapidly absorbed and utilized by the body than salts or esters, enhances taste, and reduces the need to include citric acid or other edible acids. Beta-hydroxybutyrate salts are more slowly absorbed and utilized by the body and can provide one or more electrolytes. Compositions for increasing ketone body level in a subject may contain a dietetically or pharmaceutically acceptable carrier and a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, wherein the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains from about 50.5% to 99.5% by enantiomeric equivalents of R-beta-hydroxybutyrate and from about 49.5% to about 0.5% by enantiomeric equivalents of S-beta-hydroxybutyrate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/783,844, filed Feb. 6, 2020, which is a continuation-in-part of U.S.patent application Ser. No. 16/409,501, filed May 10, 2019, now U.S.Pat. No. 10,596,131, which is a continuation-in-part of U.S. patentapplication Ser. No. 16/272,165, filed Feb. 11, 2019, now U.S. Pat. No.10,596,129, which is a continuation-in-part of U.S. patent applicationSer. No. 16/224,408, now U.S. Pat. No. 10,588,876, filed Dec. 18, 2018,which is a division of U.S. patent application Ser. No. 15/936,820,filed Mar. 27, 2018, now U.S. Pat. No. 10,245,242, which claims thebenefit of U.S. Provisional Application No. 62/590,063, filed Nov. 22,2017, the disclosures of which are incorporated by reference in theirentirety.

BACKGROUND 1. Field of the Invention

Disclosed herein are non-racemic beta-hydroxybutyrate compounds, salts,acids, and esters thereof, and compositions enriched with R-enantiomerof beta-hydroxybutyrate and methods for producing elevated blood levelsof ketone bodies in a subject.

2. Related Technology

In periods of fasting, extreme exercise, and/or low carbohydrateconsumption, glucose and glycogen stores in the body are rapidly usedand can become quickly depleted. Failure to replenish glucose stores asthey become depleted causes the body to metabolically shift to thecreation and use of ketone bodies for energy (“ketosis”). Ketone bodiescan be used by cells of the body as a fuel to satisfy the body's energyneeds, including the brain and heart. During prolonged fasting, forexample, blood ketone levels can increase to 2-3 mmol/L or more. It isconventionally understood that when blood ketones rise above 0.5 mmol/L,the heart, brain and peripheral tissues are using ketone bodies (e.g.,beta-hydroxybutyrate and acetoacetate) as the primary fuel source. Thiscondition is referred to as ketosis. At blood levels between 1.0 mmol/Land 3.0 mmol/L the condition is called “nutritional ketosis.”

Upon transitioning into ketosis, or in other words, during ketogenicmetabolism in the liver, the body uses dietary and bodily fats as aprimary energy source. Consequently, once in ketosis, one can induceloss of body fat by controlling dietary fat intake and maintaining lowcarbohydrate intake and blood level to sustain ketosis.

During ketosis, the body is in ketogenesis and essentially burning fatfor its primary fuel. The body cleaves fats into fatty acids andglycerol and transforms fatty acids into acetyl CoA molecules, which arethen eventually transformed through ketogenesis into the water-solubleketone bodies beta-hydroxybutyrate (i.e., “β-hydroxybutyrate” or “BHB”),acetoacetate (also known as acetylacetonate), and acetone in the liver.Beta-hydroxybutyrate and acetoacetate are the primary ketone bodies usedby the body for energy while acetone is removed and expelled as aby-product of ketogenesis.

The metabolism of ketone bodies is associated with several beneficialeffects, including anticonvulsant effects, enhanced brain metabolism,neuroprotection, muscle sparing properties, and improved cognitive andphysical performance. Science-based improvements in efficiency ofcellular metabolism, managed through ketone supplementation, can havebeneficial impacts on physical, cognitive health, and psychologicalhealth, and a long-term impact on health with respect to commonavoidable diseases such as obesity, cardiovascular disease,neurodegenerative diseases, diabetes, and cancer.

Despite the many health advantages of pursuing a ketogenic diet orlifestyle and maintaining a state of nutritional ketosis, there remainsignificant barriers to pursuing and maintaining a ketogenic state. Oneof these barriers is the difficulty of transitioning into a ketogenicstate. The fastest endogenous way to entering ketosis through depletingglucose stores in the body is by fasting combined with exercise. This isphysically and emotionally demanding and is extremely challenging evenfor the most motivated and disciplined.

Additionally, the transition into ketosis is often accompanied byhypoglycemia, which can cause lethargy and light-headedness in many,resulting in an uncomfortable physiological and mental state commonlyreferred to as the “low-carb flu.” In addition, many people experience adown regulation in their metabolism as the body naturally goes into an“energy-saving” mode. Some suggest that these transitory symptoms maylast as long as two to three weeks. During this transition period, if asubject consumes a meal or snack containing carbohydrates above therestrictive amount, there is an immediate termination of ketogenisis,exiting the body from its state of ketosis, as the body shifts back toglucose utilization for its primary fuel and the transition into ketosismust begin anew.

If a subject is successful in establishing ketosis, the act ofsustaining ketosis is likewise difficult, if not more difficult, due tothe need to maintain a rigid dietary ratio of carbohydrates and proteinto fats. It is further complicated by the disruption of normalelectrolyte balances that often occurs when transitioning into andmaintaining a ketogenic state. The depletion and lowering of glycogenstores in the liver and muscles lessens the ability of the body toretain water, leading to more frequent urination, and accordingly, agreater loss of electrolytes. Further, the drop in insulin levels causedby ketosis effects the rate at which certain electrolytes are extractedby the kidneys, additionally lowering electrolyte levels in the body.Negative effects of electrolyte imbalance include muscle aches, spasms,twitches and weakness, restlessness, anxiety, frequent headaches,feeling very thirsty, insomnia, fever, heart palpitations or irregularheartbeats, digestive issues such as cramps, constipation or diarrhea,confusion and trouble concentrating, bone disorders, joint pain, bloodpressure changes, changes in appetite or body weight, fatigue (includingchronic fatigue syndrome), numbness in joints, and dizziness, especiallywhen standing up suddenly.

Some compositions used to promote ketosis in a mammal include a racemicmixture of beta-hydroxybutyrate (RS-beta-hydroxybutyrate orDL-beta-hydroxybutyrate). Other compositions, such as those disclosed inU.S. Patent Publication No. 2017/0296501 to Lowery et al., contain theendogenous form of beta-hydroxybutyrate, or R-beta-hydroxybutyrate,while Lowery et al. discourage use of the non-endogenous enantiomer, orS-beta-hydroxybutyrate. Others, such as those disclosed in U.S. Pat. No.8,642,654 to Clarke et al., consist mostly or entirely of a singlebeta-hydroxybutyrate ester (3R)-hydroxybutyl (3R)-hydroxybutyrate. Otherenantiomers, such as (3R)-hydroxybutyl (3S)-hydroxybutyrate,(3S)-hydroxybutyl (3R)-hydroxybutyrate, and (3S)-hydroxybutyl(3S)-hydroxybutyrate, are mostly or entirely omitted. The omission ofenantiomers that are not the endogenous form of beta-hydroxybutyrate isbased on the view that S-beta-hydroxybutyrate (aka (3S)-hydroxybutyrate)is ineffective or even harmful.

BRIEF SUMMARY

Disclosed herein are ketogenic compositions and methods for increasingketone body level in a subject, including promoting and/or sustainingketosis in a subject. Example compositions include a non-racemic mixtureof R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, wherein thenon-racemic mixture is enriched with the R-beta-hydroxybutyrateenantiomer relative to the S-beta-hydroxybutyrate enantiomer, such as byincluding 50.5% to 99.5% by enantiomeric equivalents of theR-beta-hydroxybutyrate enantiomer and 49.5% to 0.5% by enantiomericequivalents of the S-beta-hydroxybutyrate enantiomer.

The non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate contains more of the R-beta-hydroxybutyrateenantiomer (i.e., more than 50% and less than 100%), the endogenous formproduced by a mammal, than the S-beta-hydroxybutyrate enantiomer (i.e.,less than 50% and more than 0%) in order to provide a greater and/orfaster ketogenic effect compared to a racemic mixture. Because theR-beta-hydroxybutyrate enantiomer is endogenously produced by a mammalduring ketosis, administering the R-beta-hydroxybutyrate enantiomer to asubject provides an additional quantity and/or increased blood plasmalevel that can be immediately utilized by the body, such as forproducing energy (e.g., as an alternative energy source to glucose).

Nevertheless, and contrary to conventional wisdom to minimize oreliminate S-beta-hydroxybutyrate, which is not endogenously produced bya mammal and is believed to be unnatural and potentially harmful, thenon-racemic mixture contains a significant quantity of theS-beta-hydroxybutyrate enantiomer in order to produce one or moredesired effects in the mammal, as discussed herein.

In addition, while conventional compositions typically contain polymer,oligomer, ester, or salt forms of beta-hydroxybutyrate, the non-racemicmixtures enriched with R-beta-hydroxybutyrate relative toS-beta-hydroxybutyrate can include the free acid form ofR-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate. For example, anon-racemic mixture may contain one or more salts or esters ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate in combination withR-beta-hydroxybutyric acid, and optionally S-beta-hydroxybutyric acid.Combining beta-hydroxybutyric acid with one or more beta-hydroxybutyratesalts is beneficial because it reduces electrolyte load, increasesabsorption rate, improves taste, facilitates easier formulation, andreduces the need to add citric acid or other edible acids to obtain acomposition having neutral or acidic pH.

In some embodiments, the compositions disclosed herein can be used in amethod for increasing ketone body level in a subject, includingpromoting and/or sustaining ketosis in a subject, comprisingadministering to a subject in need thereof a nutritionally orpharmaceutically effective amount of one or more compositions disclosedherein. Examples of beneficial effects of increased ketone body level ina subject include one or more of appetite suppression, weight loss, fatloss, reduced blood glucose level, improved mental alertness, increasedphysical energy, improved cognitive function, reduction in traumaticbrain injury, reduction in effect of diabetes, improvement ofneurological disorder, reduction of cancer, reduction of inflammation,anti-aging, antiglycation, reduction in epileptic seizer, improved mood,increased strength, increased muscle mass, or improved body composition.

In some embodiments, administering the non-racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate in the enantiomericratios or percentages disclosed herein provides one or more of:increased endogenous production of R-beta-hydroxybutyrate andacetoacetate; endogenous conversion of the S-beta-hydroxybutyrate intoone or both of R-beta-hydroxybutyrate and acetoacetate; endogenousconversion of the S-beta-hydroxybutyrate into fatty acids and sterols;prolonged ketosis; metabolism of the S-beta-hydroxybutyrate independentof conversion to R-beta-hydroxybutyrate and/or acetoacetate; increasedfetal development; increased growth years; reduced endogenous productionof acetone during ketosis; signaling by the S-beta-hydroxybutyrate thatmodulates metabolism of R-beta-hydroxybutyrate and glucose; antioxidantactivity; and production of acetyl-CoA.

In some embodiments, the composition may include a nutritionally orpharmaceutically acceptable carrier.

Additional features and advantages will be set forth in part in thedescription that follows, and in part will be obvious from thedescription, or may be learned by practice of the embodiments disclosedherein. It is to be understood that both the foregoing brief summary andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the embodiments disclosed herein or asclaimed.

DETAILED DESCRIPTION I. Introduction

The compound “beta-hydroxybutyrate,” also known as β-hydroxybutyrate,3-hydroxybutyrate, βHB, or BHB, is the deprotonated form ofbeta-hydroxybutyric acid, which is a hydroxycarboxylic acid having thegeneral formula CH₃CH₂OHCH₂COOH. The deprotonated form present attypical biological pH levels is CH₃CH₂OHCH₂COO⁻. The general chemicalstructure shown below represents beta-hydroxybutyrate compounds that maybe utilized in the disclosed compositions:

-   -   where,    -   X can be hydrogen, metal ion, amino cation such as from an amino        acid, alkyl, alkenyl, aryl, or acyl.

When X is a hydrogen, the compound is beta-hydroxybutyric acid. When Xis a metal ion or an amino cation, the compounds is abeta-hydroxybutyrate salt. When X is alkyl, alkenyl, aryl, or acyl, thecompounds is a beta-hydroxybutyrate ester. The foregoing compounds canbe in any desired physical form, such as crystalline, powder, solid,liquid, solution, suspension, or gel.

Unless otherwise specified, the term “salt” does not mean or imply anyparticular physical state, such as a crystalline, powder, other solidform, dissolved in water to form a liquid solution, dispersed in aliquid to form a suspension, or gel. A salt can be formed in solution,such as by at least partially neutralizing beta-hydroxybutyric acid witha strong or weak base, such as an alkali or alkaline earth metalhydroxide, carbonate, or bicarbonate, basic amino acid, and the like.

In some cases, the composition can include a mixture of one or morebeta-hydroxybutyrate salts and beta-hydroxybutyric acid(s). ProvidingR-beta-hydroxybutyrate in its acid form can be beneficial because of itsmuch quicker absorption response time compared to the salt form.Nonetheless, even though the acid form by itself is a liquid withextremely low pH and unpalatable taste, when made or combined with thesalt form(s) and where the amount of beta-hydroxybutyric acid is smallrelative to the salt form(s), the composition can still form a solid,powder or other form typical of the salt form(s). In such case, thecombined salt and acid form of BHB has acceptable pH and taste. BHBcompositions that include both salt and acid forms have advantages, suchas increased absorption rate, increased bioavailability, lowerelectrolyte load, ease of manufacture, significantly improved taste, andreduced need for citric acid or other edible acids to obtain acomposition with neutral or acidic pH. It will be appreciated thatbeneficial effects can also be provided using a mixture of BHB salt(s)and/or ester(s) and the acid form(s) of BHB.

The term “free beta-hydroxybutyric acid” means the sum ofnon-deprotonated and deprotonated beta-hydroxybutyric acid molecules. Adeprotonated beta-hydroxybutyric acid molecule generally means amolecule that has released a proton to form a hydronium ion (H₃O+) and abeta-hydroxybutyrate anion (e.g., dissolved in water).

Free beta-hydroxybutyric acid molecules are typically not deprotonatedto any significant degree when contained in a beta-hydroxybutyrate mixedsalt-acid composition in dry powder or other solid form. In such cases,the fractional amount of free beta-hydroxybutyric acid in abeta-hydroxybutyrate mixed salt-acid composition on a weight basis isthe weight of free beta-hydroxybutyric acid divided by the combinedweight of free beta-hydroxybutyric acid and beta-hydroxybutyratesalt(s). On a molar basis, the fractional amount of freebeta-hydroxybutyric acid in an beta-hydroxybutyrate mixed salt-acidcomposition are the molar equivalents of free beta-hydroxybutyric aciddivided by the sum of molar equivalents of free beta-hydroxybutyric acidand beta-hydroxybutyrate anions provided by the beta-hydroxybutyratesalt(s).

When dissolved in water, a portion of the beta-hydroxybutyric acid willtypically dissociate into beta-hydroxybutyrate anions and hydronium ions(H₃O+). As a result, beta-hydroxybutyric acid molecules can exchangeprotons and cations with dissolved beta-hydroxybutyrate salts. Forpurposes of defining the relative amounts of beta-hydroxybutyric acidand beta-hydroxybutyrate salt(s) in a beta-hydroxybutyrate mixedsalt-acid composition, dissociation of beta-hydroxybutyric acidmolecules and the exchange of protons and cations is not understood aschanging the molar ratio of free beta-hydroxybutyric acid relative tobeta-hydroxybutyrate anions from the beta-hydroxybutyrate salt(s). Thetotal quantity of free beta-hydroxybutyric acid molecules in solution isthe sum of dissolved beta-hydroxybutyric acid molecules that are notdeprotonated and beta-hydroxybutyrate anions formed by deprotonation ofbeta-hydroxybutyric acid molecules.

Stated another way, the total molar equivalents of beta-hydroxybutyricacid in solution, whether or not deprotonated, is understood to be thedifference between (i) the sum of molar equivalents of non-deprotonatedbeta-hydroxybutyric acid molecules and total molar equivalents ofbeta-hydroxybutyrate anions in solution (from all sources) and (ii) thetotal molar equivalents of cationic charge provided by cations from thebeta-hydroxybutyrate salt compounds (which equals the total molarequivalents of beta-hydroxybutyrate anions provided by thebeta-hydroxybutyrate salt(s)). Alkali metal cations such as sodium andpotassium provide 1 mole of cationic charge per mole of metal cations.Alkaline earth metal cations such as magnesium and calcium, on the otherhand, provide 2 moles of cationic charge per mole of metal cations. 1mole of deprotonated beta-hydroxybutyric acid molecules provide 1 moleof anionic charge and one mole of cationic charge.

In view of the foregoing, the molar fraction of beta-hydroxybutyric acidin solution in relation to total moles of beta-hydroxybutyrate moleculesfrom the beta-hydroxybutyrate mixed salt-acid composition in solution is[(i)-(ii) (i)], and the molar fraction of beta-hydroxybutyrate moleculesfrom the beta-hydroxybutyrate salt(s)) in solution is [(ii) (i)].Multiplying the molar fraction of each by 100 gives the percentage ofeach in solution.

By way of example, if 100 molar equivalents of beta-hydroxybutyratemixed salt-acid composition in a dry powdered state contained 5% of freenon-deprotonated beta-hydroxybutyric acid and 95% beta-hydroxybutyratesalt(s) on a molar basis, there would be essentially 5 molar equivalentsof beta-hydroxybutyric acid molecules and 95 molar equivalents ofbeta-hydroxybutyrate anions. When there is sufficient water to dissolvethe beta-hydroxybutyrate salt(s), and if a portion of thebeta-hydroxybutyric acid molecules were deprotonated, the molarequivalents of non-deprotonated beta-hydroxybutyric acid would be lessthan 5, and the molar equivalents of beta-hydroxybutyrate anions wouldbe greater than 95. The extent of deprotonation of beta-hydroxybutyricacid in solution is related to solution pH.

Whether beta-hydroxybutyrate is the R- or S-enantiomer depends on thetetrahedral orientation of the hydroxy (or oxy group in the case of anester) on the 3-carbon (beta-carbon) in relationship to the planarcarboxyl group.

Beta-hydroxybutyrate, typically R-beta-hydroxybutyrate, which is theendogenous form, can be utilized by a patient's body as a fuel sourceduring instances of low glucose levels in the subject or when apatient's body is supplemented with a usable form ofbeta-hydroxybutyrate. Beta-hydroxybutyrate is commonly referred to as a“ketone body”.

As used herein, a “ketogenic composition” is formulated to increaseketone body level in a subject, including inducing and/or sustaining astate of elevated ketone bodies at a desired level, such as ketosis, ina subject to which it is administered.

As used herein, “subject” or “patient” refers to members of the animalkingdom, including mammals, such as but not limited to, humans and otherprimates; rodents, fish, reptiles, and birds. The subject may be anyanimal requiring therapy, treatment, or prophylaxis, or any animalsuspected of requiring therapy, treatment, or prophylaxis. Prophylaxismeans that regiment is undertaken to prevent a possible occurrence, suchas where a high glucose or diabetes is identified. “Patient” and“subject” are used interchangeably herein.

The term “unit dose” refers to a dosage form that is configured todeliver a specified quantity or dose of composition or componentthereof. Example dosage forms include, but are not limited to, tablets,capsules, powders, food products, food additives, beverages (such asflavored, vitamin fortified, or non-alcoholic), beverage additives (suchas flavored, vitamin fortified, or non-alcoholic), candies, suckers,pastilles, food supplements, dietetically acceptable sprays (such asflavored mouth spray), injectables (such as an alcohol-free injectable),and suppositories. Such dosage forms may be configured to provide a fullunit dose or fraction thereof (e.g., ½, ⅓, or ¼ of a unit dose).

Another dosage form that can be used to provide a unit dose ofcomposition or component thereof is a unit dose measuring device, suchas a cup, scoop, syringe, dropper, spoon, spatula, or colonic irrigationdevice, which is configured to hold therein a measured quantity ofcomposition equaling a full unit dose or fraction thereof (e.g., ½, ⅓,or ¼ of a unit dose). For example, a bulk container, such as a carton,box, can, jar, bag, pouch, bottle, jug, or keg, containing several unitdoses of composition (e.g., 5-250 or 10-150 unit doses) can be providedto a user together with a unit dose measuring device that is configuredto provide a unit dose, or fraction thereof, of composition or componentthereof.

A kit for use in providing a composition as disclosed herein in bulkform, while providing unit doses of the composition, may comprise a bulkcontainer holding therein a quantity of composition and a unit dosemeasuring device configured to provide a unit dose, or fraction thereof,of composition or component thereof. One or more unit dose measuringdevices may be positioned inside the bulk container at the time of sale,attached to the outside of the bulk container, prepackaged with the bulkcontainer within a larger package, or provided by the seller ormanufacture for use with one or multiple bulk containers.

The kit may include instructions regarding the size of the unit dose, orfraction thereof, and the manner and frequency of administration. Theinstructions may be provided on the bulk container, prepackaged with thebulk container, placed on packaging material sold with the bulkcontainer, or otherwise provided by the seller or manufacturer (e.g., onwebsites, mailers, flyers, product literature, etc.) The instructionsfor use may include a reference on how to use the unit dose measuringdevice to properly deliver a unit dose or fraction thereof. Theinstructions may additionally or alternatively include a reference tocommon unit dose measuring devices, such as spoons, spatulas, cups, andthe like, not provided with the bulk container (e.g., in case theprovided unit dose measuring device is lost or misplaced). In such case,a kit may be constructed by the end user when following instructionsprovided on or with the bulk container, or otherwise provided by theseller regarding the product and how to properly deliver a unit dose ofcomposition, or fraction thereof.

“Ketosis” as used herein refers to a subject having blood ketone levelswithin the range of about 0.5 mmol/L and about 16 mmol/L in a subject.Ketosis may improve mitochondrial function, decrease reactive oxygenspecies production, reduce inflammation and increase the activity ofneurotrophic factors. “Keto-adaptation” as used herein refers toprolonged nutritional ketosis (>1 week) to achieve a sustainednonpathological “mild ketosis” or “therapeutic ketosis.”

In some cases, “elevated ketone body level” may not mean that a subjectis in a state of “clinical ketosis” but nevertheless has an elevatedsupply of ketones for producing energy and/or for carrying out otherbeneficial effects of ketone bodies. For example, a subject that is“ketone adapted” may not necessarily have elevated blood serum levels ofketone bodies but rather is able to utilize available ketone bodies morerapidly compared to a subject that is not “ketone adapted.” In suchcase, “elevated ketone body level” can refer to the total quantityand/or rate of ketone bodies being utilized by the subject rather thanblood plasma levels per se.

The term “short chain triglycerides” (SCT) refers to molecules having aglycerol backbone attached to three medium chain fatty acids. Shortchain fatty acids can range from 2 to 5 carbon atoms in length.Exemplary short chain fatty acids are acetic acid, propionic acid,butyric acid, isobutyric acid, valeric acid, and isovaleric acid. Anexample SCT is tributyrin.

The term “medium chain triglycerides” (MCT) refers to molecules having aglycerol backbone attached to three medium chain fatty acids. Mediumchain fatty acids can range from 6 to 12 carbon atoms in length, andmore likely 8 to 10 carbon atoms in length. Exemplary fatty acids arecaprylic acid, also known as octanoic acid, comprising 8 carbonmolecules, and capric acid, also known as decanoic acid, comprising 10carbon molecules. MCTs, medium chain fatty acids, and mono- anddi-glycerides are ketone body precursors that can provide an additionalsource for the production of ketone bodies independent ofbeta-hydroxybutyrate.

The term “long chain triglycerides” (LCT) refers to molecules having aglycerol backbone attached to three medium chain fatty acids. Long chainfatty acids can be greater than 12 carbon atoms in length.

The term “administration” or “administering” is used herein to describethe process in which the disclosed compositions are delivered to asubject. The composition may be administered in various ways includingoral, intragastric, and parenteral (referring to intravenous andintra-arterial and other appropriate parenteral routes), among others.

II. Non-Racemic Beta-Hydroxybutyrate Compositions

Compositions for increasing ketone body level in a subject, includingpromoting and/or sustaining ketosis, comprise a non-racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate enriched with theR-enantiomer (i.e., more than 50% and less than 100% by enantiomericequivalents of R-beta-hydroxybutyrate and less than 50% and more than 0%by enantiomeric equivalents of S-beta-hydroxybutyrate).

In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrateand S-beta-hydroxybutyrate contains 50.5% to 99.5%, 51% to 99%, 52% to98%, 53% to 97%, 55% to 95%, 55% to 89%, 57% to 87%, or 60% to 80% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and49.5% to 0.5%, 49% to 1%, 48% to 2%, 47% to 3%, 45% to 5%, 45% to 11%,43% to 13%, 41% to 15%, or 40% to 20% by enantiomeric equivalents of theS-beta-hydroxybutyrate enantiomer.

The non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate contains more of the R-beta-hydroxybutyrateenantiomer, the endogenous form produced by a mammal, than theS-beta-hydroxybutyrate enantiomer in order to provide a greater and/orfaster ketogenic effect compared to a racemic mixture. Because theR-beta-hydroxybutyrate enantiomer is endogenously produced by a mammalduring ketosis, administering the R-beta-hydroxybutyrate enantiomer to asubject provides an additional quantity and/or increased blood plasmalevel that can be immediately utilized by the body, such as forproducing energy (e.g., as an alternative energy source to glucose),compared to a racemic mixture of R,S-beta-hydroxybutyrate (akaDL-beta-hydroxybutyrate). The presence of the S-enantiomer can modulateand extend this effect.

Contrary to conventional wisdom to minimize or eliminateS-beta-hydroxybutyrate, which is not endogenously produced by a mammaland is believed to be unnatural and potentially harmful, the non-racemicmixture contains a significant quantity of the S-beta-hydroxybutyrateenantiomer in order to produce one or more desired effects in themammal. For example, administering S-beta-hydroxybutyrate along withR-beta-hydroxybutyrate can result in at least one of: (1) increasedendogenous production of R-beta-hydroxybutyrate and acetoacetate; (2)endogenous conversion of the S-beta-hydroxybutyrate into one or both ofR-beta-hydroxybutyrate and acetoacetate; (3) endogenous conversion ofthe S-beta-hydroxybutyrate into fatty acids and sterols; (4) prolongedketosis; (5) metabolism of the S-beta-hydroxybutyrate independent ofconversion to R-beta-hydroxybutyrate and/or acetoacetate; (6) increasedfetal development; (7) increased growth years; (8) reduced endogenousproduction of acetone during ketosis; (9) signaling by theS-beta-hydroxybutyrate that modulates metabolism ofR-beta-hydroxybutyrate and glucose; (10) antioxidant activity; and (11)production of acetyl-CoA.

The non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate can be used, for example, to produce one or moredesired effects in the subject, including but not limited to, appetitesuppression, weight loss, fat loss, reduced blood glucose level,improved mental alertness, increased physical energy, improved cognitivefunction, reduction in traumatic brain injury, reduction in effect ofdiabetes, improvement of neurological disorder, reduction of cancer,reduction of inflammation, anti-aging, antiglycation, reduction inepileptic seizer, improved mood, increased strength, increased musclemass, or improved body composition.

In some embodiments, the composition may include a nutritionally orpharmaceutically acceptable carrier.

The R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be provided invarious forms, such as salts and/or esters, together with a quantity offree acid form(s). The percent enantiomer equivalents for each ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate is defined by themolar quantity of either R-beta-hydroxybutyrate orS-beta-hydroxybutyrate divided by the total combined molar quantities ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate. The amounts of anycations forming salts and/or alcohols forming esters are excluded and donot count in determining the percent enantiomeric equivalents for eachof R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. For example, theweight contributions of cations, alcohols, or complexing agents can befactored in so as to not tip the scale relative to enantiomericequivalents of R-BHB and S-BHB.

In order to not overload the composition with R-beta-hydroxybutyrate anda high amount of precursor that is readily converted toR-beta-hydroxybutyrate, namely the mono-ester of R-1,3-butanediol andR-beta-hydroxybutyrate (i.e., (3R)-hydroxybutyl (3R)-hydroxybutyratemono-ester), the non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate shall not contain more than 88%, or 87%, or 86%,or 85% by enantiomeric equivalents of (3R)-hydroxybutyl(3R)-hydroxybutyrate mono-ester.

In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrateand S-beta-hydroxybutyrate is provided in a composition that includes adietetically or pharmaceutically acceptable carrier. Examples includepowders, liquids, tablets, capsules, food products, food additives,beverages, beverage additives, candies, suckers, pastilles, foodsupplements, sprays, injectables, and suppositories.

In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrateand S-beta-hydroxybutyrate can be provided as a salt, such as one ormore salts of alkali metals, alkaline earth metals, transition metals,amino acids, or metabolites of amino acids. Examples include lithiumsalts, sodium salts, potassium salts, magnesium salts, calcium salts,zinc salts, iron salts (as iron II and/or iron III), chromium salts,manganese salts, cobalt salts, copper salts, molybdenum salts, seleniumsalts, arginine salts, lysine salts, leucine salts, isoleucine salts,histidine salts, ornithine salts, citrulline salts, glutamine salts, andcreatine salts.

In some embodiments, the non-racemic mixture of S-beta-hydroxybutyrateand R-beta-hydroxybutyrate can be provided as one or more esters, suchas mono-, di-, tri-, oligo-, and polyesters. Examples include mono-esterof ethanol, mono-ester of 1-propanol, mono-ester of 1,2-propanediol,di-ester of 1,2-propanediol, mono-ester of 1,3-propanediol, di-ester of1,3-propanediol, mono-ester of S-, R-, or S-R-1,3-butanediol, di-esterof S-, R-, or S-R-1,3-butanediol, mono-ester of glycerin,(3S)-hydroxybutyl (3S)-hydroxybutyrate mono-ester, (3R)-hydroxybutyl(3S)-hydroxybutyrate, mono-ester, di-ester of glycerin, tri-ester ofglycerin, ester of acetoacetate, dimers, trimers, oligomers, andpolyesters containing repeating units of beta-hydroxybutyrate, andcomplex oligomers or polymers of beta-hydroxybutyrate and one or moreother hydroxy-carboxylic acids, such as lactic acid, citric acid,acetoacetic acid, quinic acid, shikimic acid, salicylic acid, tartaricacid, and malic acid, and/or beta-hydroxybutyrate and or one or morediols, such as 1,3-propanediol and 1,3-butanediol, and one or morepolyacids, such as tartaric acid, citric acid, malic acid, succinicacid, and fumaric acid. While (3R)-hydroxybutyl (3R)-hydroxybutyratemono-ester can be included, it should not exceed 88%, or 87%, or 86%, or85% by enantiomeric equivalents of the composition.

In some embodiments, the non-racemic mixture can include one or moresalt forms of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate incombination with a relatively minor amount of the acid form(s) ofR-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate. The ratio of saltto acid forms of R-beta-hydroxybutyrate is not necessarily the same asthe ratio of salt to acid forms of S-beta-hydroxybutyrate. This allowsfor more flexibility and a broader range of advantages in controllingthe pharmacokinetics and electrolyte balance of the composition.

In some embodiments, the non-racemic mixture contains less than 100% ofone or more beta-hydroxybutyrate salts and greater than 0% freebeta-hydroxybutyric acid, such as up to 99.9%, 99.8%, 99.7%, 99.6%,99.5%, 99.4%, 99.3%, 99.2%, 99.1%, 99%, 98.8%, 98.65%, 98.5%, 98.35%,98.2%, 98%, 97.75%, 97.5%, 97.25%, or 97%, and at least 75%, 80%, 85%,90%, 92%, 94%, 95%, 96%, or 97%, by molar equivalents of one or moreR-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate salts, and at least0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.35%,1.5%, 1.65%, 1.8%, 2%, 2.25%, 2.5%, 2.75%, or 3%, and less than 25%,20%, 15%, 10%, 8%, 6%, 5%, 4%, or 3%, by molar equivalents of freeR-beta-hydroxybutyric acid and/or free S-beta-hydroxybutyric acid.

In the case where the non-racemic mixture contains a high amount of theR-enantiomer relative to the S-enantiomer, it is possible to use ahigher ratio of free S-beta-hydroxybutyric acid relative toS-beta-hydroxybutyrate salt and still obtain a composition havingneutral or other desired pH. That is, even if the relative amount ofS-beta-hydroxybutyric acid is high relative to theS-beta-hydroxybutyrate salt, the overall amount of acid can berelatively small if the amount of R-beta-hydroxybutyrate salt is high.

In other embodiments, the non-racemic mixture can include one or moreester forms of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate incombination with a relatively minor amount of the acid form(s) ofR-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate. In yet otherembodiments, the non-racemic mixture can include both salt and esterforms of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate incombination with a relatively minor amount of the acid form(s) ofR-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate.

In some embodiments, the composition may include at least one mediumchain fatty acid, or a mono-, di- or triglyceride of the at least onemedium chain fatty acid, wherein the medium chain fatty acid has from 6to 12 carbons, preferably from 8 to 10 carbons. The composition mayinclude at least one short chain fatty acid, or a mono-, di- ortriglyceride of the at least one short chain fatty acid, wherein theshort chain fatty acid has less than 6 carbons. Though less preferred,the composition may include at least one long chain fatty acid, or amono-, di- or triglyceride of the at least one long chain fatty acid,having more than 12 carbons.

Examples of short chain fatty acids include acetic acid, propionic acid,butyric acid, isobutyric acid, valeric acid, and isovaleric acid.Examples of medium chain fatty acids include caproic acid, caprylicacid, capric acid, and lauric acid. Examples of long-chain fatty acidsinclude myristic acid, palmitic acid, stearic acid, arachidic acid,behenic acid, lignoceric acid, cerotic acid, omega-3 fatty acids,omega-6 fatty acids, omega-7 fatty acids, and omega-9 fatty acids.

Examples and sources of the medium chain fatty acid, or an ester thereofsuch as a medium chain triglyceride, include coconut oil, coconut milkpowder, fractionated coconut oil, palm oil, palm kernel oil, caprylicacid, capric acid, isolated medium chain fatty acids, such as isolatedhexanoic acid, isolated octanoic acid, isolated decanoic acid, mediumchain triglycerides either purified or in natural form such as coconutoil, and ester derivatives of the medium chain fatty acids ethoxylatedtriglyceride, enone triglyceride derivatives, aldehyde triglyceridederivatives, monoglyceride derivatives, diglyceride derivatives, andtriglyceride derivatives, and salts of the medium chain triglycerides.Ester derivatives optionally include alkyl ester derivatives, such asmethyl, ethyl, propyl, butyl, hexyl, etc.

The administration of a non-racemic mixture of R-beta-hydroxybutyrateand S-beta-hydroxybutyrate results in elevated and sustained bloodlevels of ketone bodies, thereby exploiting the metabolic andphysiological advantages of sustained ketosis. Raising the levels ofketone bodies in the blood provides a subject with greater flexibilityin diet options as compared to methods that aim to induce and sustainketosis based on diet alone (e.g., based on fasting and/or limitedcarbohydrate intake). For example, a subject that has been administeredan appropriate amount of a non-racemic mixture of R-beta-hydroxybutyrateand S-beta-hydroxybutyrate will be able to eat an occasionalcarbohydrate or sugar-based food without jeopardizing the ketogenicstate and shifting back into a glucose-based metabolic state. Further,such administration facilitates easier transitioning into a ketogenicstate while reducing or eliminating the detrimental effects typicallyassociated with entering ketosis.

In some embodiments, a ketogenic composition additionally includes atherapeutically effective amount of vitamin D₃. Vitamin D₃ is believedto work in conjunction with magnesium and calcium to promote good bonehealth and to prevent undesirable calcification of soft tissues. Inpreferred embodiments, vitamin D₃ is included in an amount such that anaverage daily dose of the ketogenic composition includes about 200 IU(“International Units”) to about 8000 IU, or about 400 IU to about 4000IU, or about 600 IU to about 3000 IU of vitamin D₃. In some embodiments,vitamin D₃ is included in an amount such that an average daily dose ofthe ketogenic composition includes about 5 μg to about 200 μg, or about10 μg to about 100 μg, or about 15 μg to about 75 μg of vitamin D₃.

Some embodiments also include one or more additional ketone precursorsor supplements. These additional ketone precursors or supplements mightinclude acetoacetate, ketone esters, and/or other compounds that cause arise in blood ketone levels without adding more electrolytes to thebloodstream. Other additives include metabolites that enhance the effector transport of ketone bodies into mitochondria, caffeine, theobromine,and nootropics, such as L-alpha glycerylphosphorylcholine (“alpha GPC”).

The composition may include flavoring agents that help mask theotherwise poor taste of beta-hydroxybutyrate compounds. These includeessential oils, such as peppermint, natural and artificial sweeteners,and other flavorants known in the art.

In some embodiments, ketogenic compositions may further include one ormore additional components configured to lower the hygroscopicity of thecomposition. For example, various anticaking agents, flow agents, and/ormoisture absorbers, in types and amounts that are safe for consumption,may be included. Such additional components may include one or more ofan aluminosilicate, ferrocyanide, carbonate or bicarbonate salt,silicate (e.g., sodium or calcium silicate), silica, phosphate salt(e.g., di- or tricalcium phosphate), talc, powdered cellulose, calciumcarbonate, and the like.

III. Administration

In some embodiments, the compositions disclosed herein can be used in amethod for increasing ketone body level, including promoting and/orsustaining ketosis, in a subject comprising administering to a subjectin need thereof a nutritionally or pharmaceutically effective amount ofone or more compositions disclosed herein. Examples of beneficialeffects of increasing ketone body level, including promoting and/orsustaining ketosis, in a subject include one or more of appetitesuppression, weight loss, fat loss, reduced blood glucose level,improved mental alertness, increased physical energy, improved cognitivefunction, reduction in traumatic brain injury, reduction in effect ofdiabetes, improvement of neurological disorder, reduction of cancer,reduction of inflammation, anti-aging, antiglycation, reduction inepileptic seizer, improved mood, increased strength, increased musclemass, or improved body composition.

In some embodiments, administering the non-racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate in the enantiomericratios or percentages disclosed herein provide one or more of increasedendogenous production of R-beta-hydroxybutyrate and acetoacetate;endogenous conversion of the S-beta-hydroxybutyrate into one or both ofR-beta-hydroxybutyrate and acetoacetate; endogenous conversion of theS-beta-hydroxybutyrate into fatty acids and sterols; prolonged ketosis;metabolism of the S-beta-hydroxybutyrate independent of conversion toR-beta-hydroxybutyrate and/or acetoacetate; increased fetal development;increased growth years; reduced endogenous production of acetone duringketosis; signaling by the S-beta-hydroxybutyrate that modulatesmetabolism of R-beta-hydroxybutyrate and glucose; antioxidant activity;and production of acetyl-CoA.

Ketogenic compositions described herein may be administered to a subjectin therapeutically effective dosages and/or in frequencies to induce orsustain ketosis. In some embodiments, a single dose will include anamount of non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate ranging from about 0.5 gram to about 25 grams, orabout 0.75 gram to about 20 grams, or about 1 gram to about 15 grams, orabout 1.5 grams to about 12 grams.

In some embodiments, the ketogenic compositions can include or beadministered together with other supplements, such as vitamin D₃,vitamins, minerals, nootropics, and others known in the art. Examples ofvitamins, minerals and herbal supplements that can be added to theketogenic compositions include one or more of vitamin A, vitamin C,vitamin E, niacin, vitamin B6, folic acid, 5-MTHF, vitamin B12, iodine,zinc, copper, manganese, chromium, caffeine, theobromine, theacrine,methylliberine, huperzine A, epicatechins, and enzymes.

In some embodiments, the compositions may further include one or moreshort chain fatty acids, medium chain fatty acids, long chain fattyacids, fatty acid esters, or mono-, di- or triglycerides of short,medium, or long chain fatty acids in order to provide an additionalsource of ketone bodies, as discussed herein, for sustaining ketosis fora longer period of time compared to the non-racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate by itself. In someembodiments, the composition is preferably administered such that theratio of the non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate to short, medium, or long chain fatty acid (orester thereof) ranges from about 4:1 to about 1:4, or from about 2:1 toabout 1:2, or from about 1.5:1 to about 1:1.5.

In some embodiments, the subject preferably follows a ketogenic dietthat restricts intake of carbohydrates and protein during the period ofadministration of the composition. In one example embodiment, thesubject may restrict the dietary intake to a ratio of about 65% fat,about 25% protein, and about 10% carbohydrates. The resultingtherapeutic ketosis provides a rapid and sustained keto-adaptation as ametabolic therapy for a wide range of metabolic disorders, and providesnutritional support for therapeutic fasting, weight loss, andperformance enhancement. As such, the composition is typicallyadministered once per day, twice per day, or three times per day to asubject desiring to promote and/or sustain a state of ketosis.

In a preferred embodiment, ketogenic compositions can be administeredvia oral administration in solid and/or powdered form, such as in apowdered mixture (e.g., powder filled gelatin capsules), hard-pressedtablets, or other oral administration route known to those skilled inthe art.

In some embodiments, multiple doses of the composition are administeredover a period of time. The frequency of administration of thecomposition can vary depending on any of a variety of factors, such astiming of treatment from previous treatments, objectives of thetreatment, and the like. The duration of administration of thecomposition (e.g., the period of time over which the agent isadministered), can vary depending on any of a variety of factors,including subject response, desired effect of treatment, etc.

The amount of the composition to be administered can vary according tofactors such as the degree of susceptibility of the individual, the age,sex, and weight of the individual, idiosyncratic responses of theindividual, and the like. The “therapeutically effective amount” is thatamount necessary to promote a therapeutically effective result in vivo(i.e., therapeutic ketosis). In accordance with the present disclosure,a suitable single dose size is a dose that is capable of preventing oralleviating (reducing or eliminating) a symptom in a patient whenadministered one or more times over a suitable time period.

The amount of composition administered will depend on potency,absorption, distribution, metabolism, and excretion rates of unusedketone bodies, electrolytes, the method of administration, and theparticular disorder being treated, as well as other factors known tothose of skill in the art. The dose should be sufficient to affect adesirable response, such as a therapeutic or prophylactic responseagainst a particular disorder or condition, taking into account theseverity of the condition to be alleviated. The compounds may beadministered once, or may be divided and administered over intervals oftime. It is to be understood that administration may be adjustedaccording to individual need and professional judgment of a personadministrating or supervising the administration of the compositions.

IV. Examples

The following is a description of exemplary non-racemic mixtures ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate compositions and otherketogenic compositions useful for raising ketone levels in a subject,including inducing and/or sustaining a ketogenic state in a subject towhich they are administered. It should be appreciated that thebeta-hydroxybutyrate compounds described in the examples can be in theform of salts, esters, dimers, trimers, oligomers, and polymers, asdiscussed herein. The important thing from the standpoint of theexamples is the enantiomeric percentages or ratios ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate.

In some cases, the compositions can be a blend of beta-hydroxybutyratesalts, blend of beta-hydroxybutyrate esters, blend ofbeta-hydroxybutyrate salts and esters, blend of beta-hydroxybutyratesalts and free beta-hydroxybutyric acid(s), blend ofbeta-hydroxybutyrate esters and free beta-hydroxybutyric acid(s), orblend of beta-hydroxybutyrate salts, beta-hydroxybutyrate esters, andfree beta-hydroxybutyric acid(s), to provide a desired electrolytebalance, taste and/or pharmacokinetic response. The compositions canalso be combined with short, medium, or long chain fatty acids, esters,glycerides, and other supplements as disclosed herein to provide adesired level of elevated ketone bodies and other effects.

Example 1

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 51% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and49% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes more of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is acceleratedfor a given dosage as compared to the same dosage of racemic mixture. Onthe other hand, including the S-beta-hydroxybutyrate enantiomer providesfor a longer state of ketosis and/or other benefits as disclosed herein.

The non-racemic mixture is readily administered as a ketogeniccomposition, such as in powder form as a dietary supplement mixed withfood or drink, in the form of one or more capsules or tablets, or inliquid form such as a mouth spray.

Example 2

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 52% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and48% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes more of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is acceleratedfor a given dosage as compared to the same dosage of racemic mixture. Onthe other hand, including the S-beta-hydroxybutyrate enantiomer providesfor a longer state of ketosis and/or other benefits as disclosed herein.

Example 3

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 53% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and47% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes more of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is acceleratedfor a given dosage as compared to the same dosage of racemic mixture. Onthe other hand, including the S-beta-hydroxybutyrate enantiomer providesfor a longer state of ketosis and/or other benefits as disclosed herein.

Example 4

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 55% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and45% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes more of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is acceleratedfor a given dosage as compared to the same dosage of racemic mixture. Onthe other hand, including the S-beta-hydroxybutyrate enantiomer providesfor a longer state of ketosis and/or other benefits as disclosed herein.

Example 5

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 57% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and43% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes more of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is acceleratedfor a given dosage as compared to the same dosage of racemic mixture orthe non-racemic mixture of Examples 1-4. On the other hand, includingthe S-beta-hydroxybutyrate enantiomer provides for a longer state ofketosis and/or other benefits as disclosed herein, as compared to acomposition containing 90-100% by enantiomeric equivalents of theR-beta-hydroxybutyrate enantiomer.

Example 6

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 59% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and41% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes more of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is acceleratedfor a given dosage as compared to the same dosage of racemic mixture orthe non-racemic mixtures of Examples 1-5. On the other hand, includingthe S-beta-hydroxybutyrate enantiomer provides for a longer state ofketosis and/or other benefits as disclosed herein, as compared to acomposition containing 90-100% by enantiomeric equivalents of theR-beta-hydroxybutyrate enantiomer.

Example 7

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 65% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and35% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes more of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is acceleratedfor a given dosage as compared to the same dosage of racemic mixture orthe non-racemic mixtures of Examples 1-6. On the other hand, includingthe S-beta-hydroxybutyrate enantiomer provides for a longer state ofketosis and/or other benefits as disclosed herein, as compared to acomposition containing 90-100% by enantiomeric equivalents of theR-beta-hydroxybutyrate enantiomer.

Example 8

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 70% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and30% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes more of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is acceleratedfor a given dosage as compared to the same dosage of racemic mixture orthe non-racemic mixtures of Examples 1-7. On the other hand, includingthe S-beta-hydroxybutyrate enantiomer provides for a longer state ofketosis and/or other benefits as disclosed herein, as compared to acomposition containing 90-100% by enantiomeric equivalents of theR-beta-hydroxybutyrate enantiomer.

Example 9

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 75% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and25% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes more of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is acceleratedfor a given dosage as compared to the same dosage of racemic mixture orthe non-racemic mixtures of Examples 1-8. On the other hand, includingthe S-beta-hydroxybutyrate enantiomer provides for a longer state ofketosis and/or other benefits as disclosed herein, as compared to acomposition containing 90-100% by enantiomeric equivalents of theR-beta-hydroxybutyrate enantiomer.

Example 10

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 80% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and20% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes more of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is acceleratedfor a given dosage as compared to the same dosage of racemic mixture orthe non-racemic mixtures of Examples 1-9. On the other hand, includingthe S-beta-hydroxybutyrate enantiomer provides for a longer state ofketosis and/or other benefits as disclosed herein, as compared to acomposition containing 90-100% by enantiomeric equivalents of theR-beta-hydroxybutyrate enantiomer.

Example 11

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 85% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and15% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes more of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is acceleratedfor a given dosage as compared to the same dosage of racemic mixture orthe non-racemic mixtures of Examples 1-10. On the other hand, includingthe S-beta-hydroxybutyrate enantiomer provides for a longer state ofketosis and/or other benefits as disclosed herein, as compared to acomposition containing 90-100% by enantiomeric equivalents of theR-beta-hydroxybutyrate enantiomer.

Example 12

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 89% byenantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and11% by enantiomeric equivalents of the S-beta-hydroxybutyrateenantiomer. Because the non-racemic mixture includes more of theR-beta-hydroxybutyrate enantiomer, the onset of ketosis is acceleratedfor a given dosage as compared to the same dosage of racemic mixture orthe non-racemic mixtures of Examples 1-11. On the other hand, includingthe S-beta-hydroxybutyrate enantiomer provides for a longer state ofketosis and/or other benefits as disclosed herein, as compared to acomposition containing 90-100% by enantiomeric equivalents of theR-beta-hydroxybutyrate enantiomer.

Example 13

A non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate is prepared by mixing one or moreR-beta-hydroxybutyrate compounds with a racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide from 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 99.5% by enantiomericequivalents of the R-beta-hydroxybutyrate enantiomer and 10%, 9%, 8%,7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% by enantiomeric equivalents of theS-beta-hydroxybutyrate enantiomer, with the proviso that the non-racemicmixture does not contain more than 88%, or 87%, or 86%, or 85% byenantiomeric equivalents of (3R)-hydroxybutyl (3R)-hydroxybutyratemono-ester (i.e., the mono-ester of R-1,3-butanediol andR-beta-hydroxybutyrate). Because the non-racemic mixture includes moreof the R-beta-hydroxybutyrate enantiomer, the onset of ketosis isaccelerated for a given dosage as compared to the same dosage of racemicmixture or the non-racemic mixtures of Examples 1-12.

Example 14

Any of the foregoing examples is modified by combining the non-racemicmixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with adietetically or pharmaceutically acceptable carrier.

Example 15

Any of the foregoing examples is modified by combining the non-racemicmixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one ormore medium chain triglycerides and/or one or more medium chain fattyacids and/or one or more mono- or diglycerides of medium chain fattyacids.

Example 16

Any of the foregoing examples is modified by combining the non-racemicmixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one ormore short chain triglycerides and/or one or more short chain fattyacids and/or one or more mono- or diglycerides of short chain fattyacids.

Example 17

Any of the foregoing examples is modified by combining the non-racemicmixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one ormore long chain triglycerides and/or one or more long chain fatty acidsand/or one or more mono- or diglycerides of long chain fatty acids.

Example 18

Any of the foregoing examples is modified by combining the non-racemicmixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one ormore supplements, such as vitamin D₃, vitamins, minerals, and othersknown in the art.

Example 19

Any of the foregoing examples is modified by including one or more saltsof R-beta-hydroxybutyrate and S-beta-hydroxybutyrate and at least one ofR-beta-hydroxybutyric acid or S-beta-hydroxybutyric acid to provide amixture of R- and S-beta-hydroxybutyrate salts and free R- and/orS-beta-hydroxybutyric acid(s), where the mixture contains less than 100%of the one or more beta-hydroxybutyrate salts and greater than 0% of thefree beta-hydroxybutyric acid(s), including up to 99.9%, 99.8%, 99.7%,99.6%, 99.5%, 99.4%, 99.3%, 99.2%, 99.1%, 99%, 98.8%, 98.65%, 98.5%,98.35%, 98.2%, 98%, 97.75%, 97.5%, 97.25%, or 97% by molar equivalentsof one or more R-beta-hydroxybutyrate and/or S-beta-hydroxybutyratesalts, and at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%,0.9%, 1%, 1.2%, 1.35%, 1.5%, 1.65%, 1.8%, 2%, 2.25%, 2.5%, 2.75%, or 3%,by molar equivalents of free R-beta-hydroxybutyric acid and/or freeS-beta-hydroxybutyric acid.

Example 20

Any of the foregoing examples is modified by including one or moreesters of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate and at leastone of R-beta-hydroxybutyric acid or S-beta-hydroxybutyric acid toprovide a mixture of R- and S-beta-hydroxybutyrate ester forms and freeR- and/or S-beta-hydroxybutyric acid(s), where the non-racemic mixturecontains less than 100% of the one or more beta-hydroxybutyrate estersand greater than 0% free beta-hydroxybutyric acid.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

1. A composition for administering ketone bodies to a subject,comprising: a non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate containing more than 50% and less than 100% byenantiomeric equivalents of R-beta-hydroxybutyrate and less than 50% andmore 0% by enantiomeric equivalents of S-beta-hydroxybutyrate, whereinthe non-racemic mixture of R-beta-hydroxybutyrate andS-beta-hydroxybutyrate includes: at least one R-beta-hydroxybutyratesalt; at least one S-beta-hydroxybutyrate salt; and at least one of R-or S-beta-hydroxybutyric acid, wherein the non-racemic mixture comprises75% to 99.9% by molar equivalents of combined R-beta-hydroxybutyrate andS-beta-hydroxybutyrate salts, wherein the non-racemic mixture comprises0.1% to 25% by molar equivalents of the at least one of R- orS-beta-hydroxybutyric acid.
 2. The composition of claim 1, wherein thenon-racemic mixture contains from 50.5% to 99.5% by enantiomericequivalents of R-beta-hydroxybutyrate and 49.5% to 0.5% by enantiomericequivalents of S-beta-hydroxybutyrate.
 3. The composition of claim 1,wherein the non-racemic mixture contains from 51% to 99% by enantiomericequivalents of R-beta-hydroxybutyrate and 49% to 1% by enantiomericequivalents of S-beta-hydroxybutyrate.
 4. The composition of claim 1,wherein the non-racemic mixture contains from 52% to 98% by enantiomericequivalents of R-beta-hydroxybutyrate and 48% to 2% by enantiomericequivalents of S-beta-hydroxybutyrate.
 5. The composition of claim 1,wherein the non-racemic mixture contains from 53% to 97% by enantiomericequivalents of R-beta-hydroxybutyrate and 47% to 3% by enantiomericequivalents of S-beta-hydroxybutyrate.
 6. The composition of claim 1,wherein the non-racemic mixture comprises 80% to 99.9% by molarequivalents of combined R-beta-hydroxybutyrate andS-beta-hydroxybutyrate salts and 20% to 0.1% by molar equivalents ofR-beta-hydroxybutyric acid and/or S-beta-hydroxybutyric acid.
 7. Thecomposition of claim 1, wherein the non-racemic mixture comprises 85% toabout 99.9% by molar equivalents of combined R-beta-hydroxybutyrate andS-beta-hydroxybutyrate salts and 15% to 0.1% by molar equivalents ofR-beta-hydroxybutyric acid and/or S-beta-hydroxybutyric acid.
 8. Thecomposition of claim 1, wherein the non-racemic mixture comprises 90% to99.9% by molar equivalents of combined R-beta-hydroxybutyrate andS-beta-hydroxybutyrate salts and 10% to 0.1% by molar equivalents ofR-beta-hydroxybutyric acid and/or S-beta-hydroxybutyric acid.
 9. Thecomposition of claim 1, wherein the non-racemic mixture comprises atleast one lithium, sodium, potassium, calcium, magnesium, or amino acidsalt of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate.
 10. Thecomposition of claim 1, further comprising at least one short chainfatty acid having less than 6 carbons, or a mono-, di- or triglycerideof the at least one short chain fatty acid.
 11. The composition of claim1, further comprising at least one supplement selected from vitamin,mineral, nootropic, and herbal supplement.
 12. A composition foradministering ketone bodies to a subject, comprising: a non-racemicmixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate containingmore than 50% and less than 100% by enantiomeric equivalents ofR-beta-hydroxybutyrate and less than 50% and more 0% by enantiomericequivalents of S-beta-hydroxybutyrate, wherein the non-racemic mixtureof R-beta-hydroxybutyrate and S-beta-hydroxybutyrate includes: at leastone R-beta-hydroxybutyrate salt or ester; at least oneS-beta-hydroxybutyrate salt or ester; and at least one of R- orS-beta-hydroxybutyric acid, wherein the non-racemic mixture comprises75% to 99.9% by molar equivalents of combined R-beta-hydroxybutyrate andS-beta-hydroxybutyrate salts, wherein the non-racemic mixture comprises0.1% to 25% by molar equivalents of the at least one of R- orS-beta-hydroxybutyric acid, and wherein the composition is provided asor in a tablet, capsule, powder, food product, food additive, flavoredbeverage, vitamin fortified beverage, non-alcoholic beverage, flavoredbeverage additive, vitamin fortified beverage additive, non-alcoholicbeverage additive, candy, sucker, pastille, food supplement, flavoredmouth spray, or suppository.
 13. The composition of claim 12, whereinthe non-racemic mixture contains from 50.5% to 99.5% by enantiomericequivalents of R-beta-hydroxybutyrate and 49.5% to 0.5% by enantiomericequivalents of S-beta-hydroxybutyrate.
 14. The composition of claim 12,wherein the non-racemic mixture comprises 85% to 99.9% by molarequivalents of combined R-beta-hydroxybutyrate andS-beta-hydroxybutyrate salts and 15% to 0.1% by molar equivalents ofR-beta-hydroxybutyric acid and/or S-beta-hydroxybutyric acid.
 15. Thecomposition of claim 12, wherein the non-racemic mixture comprises atleast one lithium, sodium, potassium, calcium, magnesium, or amino acidsalt of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate, andwherein the composition is a powder.
 16. The composition of claim 12,further comprising at least one supplement selected from vitamin,mineral, nootropic, and herbal supplement.
 17. A composition foradministering ketone bodies to a subject, comprising: a dietetically orpharmaceutically acceptable carrier selected from the group consistingof tablet, capsule, powder, food product, food additive, flavoredbeverage, vitamin fortified beverage, non-alcoholic beverage, flavoredbeverage additive, vitamin fortified beverage additive, non-alcoholicbeverage additive, candy, sucker, pastille, food supplement, flavoredmouth spray, and suppository; and a non-racemic mixture ofR-beta-hydroxybutyrate and S-beta-hydroxybutyrate containing more than50% and less than 100% by enantiomeric equivalents ofR-beta-hydroxybutyrate and less than 50% and more 0% by enantiomericequivalents of S-beta-hydroxybutyrate, wherein the non-racemic mixtureof R-beta-hydroxybutyrate and S-beta-hydroxybutyrate includes: at leastone R-beta-hydroxybutyrate salt or R-beta-hydroxybutyrate ester; atleast one S-beta-hydroxybutyrate salt or S-beta-hydroxybutyrate ester;and at least one of R- or S-beta-hydroxybutyric acid, wherein thenon-racemic mixture comprises 75% to 99.9% by molar equivalents ofcombined R-beta-hydroxybutyrate and S-beta-hydroxybutyrate salts,wherein the non-racemic mixture comprises 0.1% to 25% by molarequivalents of the at least one of R- or S-beta-hydroxybutyric acid. 18.A kit for administering ketone bodies to a subject, comprising: acomposition as in claim 1; a container in which the composition isplaced; and a measuring device configured to hold therein a unit dose,or fraction thereof, of the composition, wherein a unit dose of thecomposition contains about 0.5 g to about 25 g of the non-racemicmixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate.
 19. Thekit of claim 18, wherein the container is selected from the groupconsisting of carton, box, can, jar, bag, pouch, bottle, jug, and keg.20. The kit of claim 18, wherein the measuring device is selected fromthe group consisting of cup, scoop, syringe, dropper, spatula, spoon,and colonic irrigation device.